CHAPTER OUTLINE

Inherited metabolic diseases (IMDs), also known as inborn errors of metabolism, are inherited conditions that develop as a result of mutations that affect the function of proteins. The majority of IMDs are monogenic conditions and the mutant proteins are enzymes, but others involve structural proteins, receptors, hormones or transport proteins. Although they are inherited, not all IMDs present in the newborn period: some present later in childhood or not until adult life.

Inherited metabolic diseases are individually rare. Of those that present in childhood, the commonest, such as phenylketonuria (PKU) and medium chain acyl-CoA dehydrogenase deficiency (MCADD), have an incidence of 1 in 10 000. However, collectively, the IMDs that present in childhood are thought to occur with an incidence of 1 in 750 live births, although the true incidence is unknown, as no newborn screening programme is comprehensive, and many of these conditions go undiagnosed. More diagnoses are being secured with advancing diagnostic techniques, such as tandem mass spectrometry, and the growing awareness of these disorders by clinicians. Similarly, the therapeutic options are continuing to expand, increasing the pressure to detect cases at an earlier stage. Importantly, improving treatments leads to longer survival that, in turn, may present new clinical challenges such as the management of pregnancy in an affected mother. Altering the natural history of a condition may also reveal previously unknown long-term complications.

Inherited metabolic diseases may present at any age. However, there are key times when presentation is more common, either owing to the individual having to survive biochemically without the support of the mother’s placenta, or to additional metabolic stresses at that particular time.

Many IMDs present in the neonatal period. They may be considered in four broad categories: problems of synthesis and breakdown of complex molecules; intoxications; energy deficiency states, and seizure disorders.

Many complex molecules are integral to cell-to-cell communication and ordered patterning within the developing embryo. Failure to make these complex molecules can, therefore, result in disordered embryogenesis, presenting as a dysmorphic neonate at birth. An example is Zellweger syndrome, the most severe of the peroxisomal biogenesis defects. Affected neonates have a typical appearance, with a large fontanelle, prominent forehead and hypertelorism, hypotonia, hepatomegaly and calcific stippling, particularly of the knees and shoulders, on X-rays. The principle defect in peroxisomal disorders lies within the PEX genes, which encode the peroxin proteins critical for the targeting and importing of peroxisomal enzymes and proteins into peroxisomes, resulting in multiple enzyme deficiencies. This group of disorders is diagnosed by the analysis of very long chain fatty acids (VLCFAs), which are elevated in plasma owing to the block in their oxidation, which is a peroxisomal process. Management remains supportive, rather than curative.

Smith–Lemli–Opitz syndrome is another example of a synthetic defect. It results from a block in the penultimate step in cholesterol synthesis, 3β-hydroxysterol-Δ7-reductase. The production of cholesterol, an essential component of cell membranes, is decreased with marked elevation of its precursor 7-dehydrocholesterol (7-DHC) in body fluids and tissues. The characteristic dysmorphology includes anteverted nares, low-set ears, micrognathia, ptosis and microcephaly. Other features include syndactyly of the 2nd and 3rd toes, present in 98% of patients, genital and renal anomalies, learning difficulties and severe failure to thrive. Dietary cholesterol replacement and statin treatment have been used with the aim of inhibiting cholesterol synthesis and reducing accumulation of 7-DHC; no convincing effects have been seen with either approach, but this may be because the phenotype is determined by the in utero availability of cholesterol.

Problems with the breakdown of complex molecules result in storage disorders. These tend not to be apparent at birth, but rather become so with time as the substance(s) stored in excess begins to affect structure and function. For example, affected children with Hurler syndrome (mucopolysaccharidosis type I, MPSI) appear normal at birth, but the gradual accumulation of glycosaminoglycans over time produces the typical coarsening of the features, corneal clouding, organomegaly and dysostosis multiplex (distortion of the normal bony architecture secondary to storage material) that are characteristic of the condition. However, it is parental concerns about delayed development, rather than the coarse features, that usually bring these patients to medical attention. Storage disorders in which dysmorphology and organomegaly are often present in the first month of life include I-cell disease, infantile sialic acid storage disease and early infantile GM1 gangliosidosis.

Intoxication is the classic presentation of inherited metabolic disorders. An unremarkable period immediately after birth is followed by increasing clinical abnormality as the baby feeds, and toxic metabolites, which cannot be broken down because of the metabolic block, accumulate. Prior to birth, these toxic metabolites are cleared via the placenta. Typically, clinical features develop within 48–72 h after birth, but can take considerably longer. Phenylketonuria (phenylalanine hydroxylase deficiency) is an intoxication, but the first signs of the condition do not usually develop until 6–12 months after birth when motor developmental milestones are not met. Phenylketonuria (PKU) also illustrates two other features of inherited metabolic diseases affecting enzymes: accumulation of the substrate of the defective enzyme may lead to increased metabolism via alternative, normally minor, pathways by a mass action effect (phenylalanine is transaminated to phenylpyruvate and phenylketones), and there may be deficiency of the normal product of the enzyme (in this case, tyrosine). Both of these may contribute to the clinical presentation.

Galactosaemia (galactose 1-phosphate uridyltransferase deficiency) usually presents a little later, at the end of the first week of life, with jaundice due to conjugated bilirubinaemia, hepatomegaly, coagulopathy and characteristic ‘oil drop’ cataracts. The diagnosis is made by measuring the enzyme activity in red cells. The exact pathogenesis is not fully elucidated, but restriction of galactose and lactose (a disaccharide of glucose and galactose) is effective in reversing the liver toxicity. However, the diet does not prevent all adverse effects of the disease and it is clear that endogenous galactose production is significant. As with many IMDs, some infants present later than the neonatal period, with the renal effects of galactosaemia, namely proximal tubulopathy and rickets, rather than the hepatic consequences. A similar difference in presentation is seen in tyrosinaemia type 1, with an early hepatotoxic picture not unlike galactosaemia and a later Fanconi-type presentation due to nephrotoxicity. The key diagnostic marker in tyrosinaemia type 1 is the detection of succinylacetone on urinary organic acid analysis.

The key diagnostic marker is a raised plasma lactate concentration but, in practice, secondary hyperlactataemia (due, e.g. to hypoxia, hypovolaemia, hypotension etc.) is more common. The distinguishing diagnostic clue is the absence of ketones in the secondary elevations. Spurious elevation may result from squeezing the arm to elevate the vein prior to venepuncture. A free-flowing sample is required and an arterial stab should be used if a free-flowing sample cannot be obtained otherwise. Further evidence may be gleaned from measuring lactate in the cerebrospinal fluid (CSF), which reflects brain lactate over days rather than at that specific time. Secondary elevations of CSF lactate are seen in primary brain infections such as encephalitis and meningitis, and following seizures.

In certain disorders, energy deficiency only becomes apparent when feeding is interrupted. Neonates with fatty acid oxidation defects remain asymptomatic while fed, but can develop hypoketotic hypoglycaemia during prolonged fasting or intercurrent infections. The commonest fat oxidation defect, MCADD, usually presents much later, at around the age of one year, but a subgroup present in the first few days of life, before feeding becomes established, most commonly if they are breast fed. Neonatal glycogen stores are more rapidly exhausted than those in older infants and adults, requiring mobilization of fat stores for energy. Fats cannot be directly utilized by the brain, requiring conversion in the liver to ketones, which can be. Failure to produce ketones results in encephalopathy as a result of a combination of hypoglycaemia and the accumulation of acylcarnitines. Clinically evident hypoglycaemia is a late feature: treatment, either with oral glucose polymer or intravenous 10% dextrose, should be started before it occurs.

Weaning is a time when new dietary components may first be encountered, and if any one of their metabolic pathways is blocked, clinical features may develop. Weaning may also result in greater intake of the particular substrate whose metabolism is compromised, e.g. protein. If the relevant metabolic pathway is unable to cope with the increased load, the threshold for the development of clinical features may be breached. An example of the latter is a partial urea cycle defect. Prior to weaning, protein intake may have been within the tolerance of the compromised pathway, but with the addition of solids, greater quantities of protein can be ingested. If, as a result, the pathway’s capacity is exceeded, hyperammonaemia will ensue. A similar effect is seen in children with hyperphenylalaninaemia detected on newborn screening. A decision is usually made to monitor concentrations to see if the phenylalanine increases with greater food intake, particularly around the time of weaning.

Hereditary fructose intolerance (aldolase B deficiency) does not present until an infant is exposed to fructose, which typically occurs around the time of weaning when pureed fruit is introduced; the sucrose in fruit is broken down to fructose and glucose. There is no fructose or sucrose in breast milk or formula milk. In the affected patient, fructose 1-phosphate accumulates, inhibiting glucose production, promoting hypoglycaemia and depleting inorganic phosphate, thereby reducing ATP production. Clinically, the first features are nausea and vomiting with postprandial hypoglycaemia. If the condition is not recognized, and fructose ingestion persists, the infant will fail to thrive and may develop liver and kidney failure. Confirmatory enzymology requires liver biopsy; however, in some patients a clinical diagnosis can be made on the basis of a history of exposure to fructose and reversal of symptoms after elimination of sources of fructose from the diet. The diagnosis may then be confirmed by genotyping.

Infancy is a time when there is a considerable risk of infections, as the body is exposed to numerous infectious agents for the first time and the immune system is still developing. Infection causes increased metabolic stress; patients with known IMDs may decompensate and others may present for the first time. Some IMDs show seasonal variation in presentation: for example, MCADD presents more frequently in the autumn and winter months, because of the increase in infections at this time of year.

Glutaric aciduria type I (GA-I) is an autosomal recessive defect in lysine catabolism. Affected infants may have large heads but minimal neurological signs prior to catastrophic metabolic decompensation around the end of the first year, usually precipitated by an infection. Such decompensation causes damage to the basal ganglia, with resultant irreversible dystonia and movement disorder. In presymptomatic siblings, prospective early aggressive management of intercurrent illnesses with antibiotics, protein (lysine) restriction, carnitine supplements and hyperalimentation with glucose polymer or intravenous dextrose, can reduce the incidence of decompensation and subsequent neurological sequelae. Measurement of urinary organic acids shows elevated glutarate and 3-hydroxyglutarate in this condition. Occasional patients have been described with classic histories and abnormal enzymology in fibroblast studies without the typical urine abnormalities; plasma acylcarnitine analysis may show reduced free carnitine and a glutarylcarnitine peak, but may be normal in such patients.

Infants may present with IMDs towards the end of the first year, when growth slows. On average, a baby will put on just under 7 kg in weight in the first year of life, compared with 2 kg each subsequent year during childhood. This means that for the same protein intake, more will need to be catabolized, as less is needed for growth. This increased pressure on an affected metabolic pathway may result in decompensation.

Puberty is recognized as a difficult time for teenagers and rebellion affects all areas of life, including caring for their health. Patients with significant IMDs may break their diets or fail to take their medication in an attempt to be ‘normal’. Both can precipitate decompensation. However, new presentations are also seen at this time, probably as a result of changes in growth and the hormonal milieu. For girls with urea cycle defects, it is well recognized that following menarche, symptoms may fluctuate in time with the menstrual cycle, being worse in the few days leading up to, and including, the start of the period. The use of hormonal therapy to suppress ovulation and menstruation has proven helpful in some patients.

Inherited metabolic diseases are often considered to be paediatric conditions, but it must be remembered that they can present at any age. This may be owing to the defect being less severe so that an individual’s metabolism has not previously been sufficiently stressed to provoke decompensation. Patients with partial ornithine transcarbamoylase (OTC) deficiency, the commonest of the urea cycle defects, may remain asymptomatic throughout childhood and only present in adult life. Some adults may not have been exposed previously to sufficient quantities of metabolites they cannot deal with. Some adults with hereditary fructose intolerance will have learned at an early age that sweet, sugary foods make them feel unwell and will subconsciously avoid them. Many patients with this condition have perfect dentition owing to their self-imposed diet.

For some IMDs, presentation differs between adults and children. The severe form of X-linked adrenoleukodystrophy (ALD) usually presents at 5–10 years with progressive neurological deterioration, ultimately leading to spastic quadriplegia, seizures, vegetative state and death. More than 90% of affected boys have adrenal insufficiency. However, adrenal involvement may precede, or follow, neurological symptoms by years. There is wide phenotypic variability within families, and another family member may not present until adulthood. The cerebral form in adults is extremely rare, accounting for < 5% of all cases. The commoner adult presentation is adrenomyeloneuropathy (AMN), with a slowly progressive neurological picture mimicking spinal cord syndrome, with spastic gait and difficulty voiding urine. Some 10% of patients have only adrenal involvement, and 10% remain asymptomatic. Adrenoleukodystrophy is the commonest peroxisomal disorder. The defective adrenoleukodystrophy protein (ALDP) is thought to play a role in the uptake of VLCFAs across the peroxisomal membrane, but the exact pathophysiology is not completely understood. The use of Lorenzo’s oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) reduces the accumulation of the VLCFAs, but fails to prevent neurological decline in symptomatic patients. It appears to have a role in asymptomatic boys reducing the risk of developing abnormalities apparent on magnetic resonance imaging. Bone marrow transplantation can be performed to stabilize cerebral ALD in the very early stages of demyelination. The varied phenotype is not explained by differences in genotype, as family members with different manifestations of the condition will usually have the same mutation.

Adrenoleukodystrophy also demonstrates another variation in adult presentation, that of the manifesting heterozygote. This is seen in some X-linked conditions where a carrier female develops symptoms. Two-thirds of females carrying an ALD gene mutation have some degree of neurological involvement, ranging from brisk reflexes and mild abnormalities on clinical examination to a full-blown AMN-like picture. This may be misdiagnosed as multiple sclerosis.

A similar phenomenon is seen in Fabry disease (α-galactosidase deficiency). Deposition of glycosphingolipids in blood vessel walls, heart, kidneys, skin and autonomic ganglia produces cerebrovascular disease, cardiac disease, nephropathy, angiokeratoma, corneal dystrophy and acroparaesthesia (severe pain in the extremities). It was believed that the majority of female carriers were entirely asymptomatic throughout life, but it is now clear that one-third of female carriers have significant symptoms, which may be so severe as to warrant treatment. One explanation for the spectrum of severity is the random inactivation of the X chromosome in cells – lyonization. If sufficient numbers of the unaffected X chromosomes are suppressed, a significant number of cells will have a functioning, affected X chromosome. The resulting enzyme function may be low enough for symptoms to develop.

A significant number of IMDs present for the first time in adulthood. The classic mitochondrial syndromes that led to the recognition of mitochondrial DNA (mtDNA) mutations and their role in pathology are all primarily adult presentations: an example is Leber hereditary optic neuroretinopathy, presenting most commonly in the third decade of life with bilateral, painless central vision loss.

The IMDs that typically present only in adult life usually involve the accumulation of a toxic substance that, although it begins at birth, takes many years to become manifest. Important examples include heterozygous familial hypercholesterolaemia (homozygotes usually present with xanthomata or coronary disease in the second decade), familial combined hyperlipidaemia and primary (genetic) haemochromatosis (excepting the rare neonatal variant). All these conditions are discussed elsewhere in this book.

The physiological stresses of pregnancy may precipitate crises in women with IMDs so meticulous care is required to ensure the best outcome for the mother and baby. Some women develop symptoms in pregnancy because they carry an affected child, although they do not have the condition themselves. The classic examples of this are the long chain fatty acid oxidation defects, long chain hydroxyl-acyl-CoA dehydrogenase deficiency (LCHADD) and very long chain acyl-CoA dehydrogenase deficiency (VLCADD). These conditions are recessively inherited and the mother, therefore, is an obligate carrier with 50% enzyme activity, which is compatible with normal life and function. Clinical manifestation of most IMDs only occurs if activity is < 5%. However, the mother also has to combat the metabolic stresses of pregnancy, which increase the load on the pathway. If the fetus is affected, she will also have to break down the long chain acylcarnitines that the fetus is producing owing to the block in its metabolism. Such women do not present with the typical hypoketotic hypoglycaemia seen in affected infants, but liver function is impaired, precipitating HELLP (hepatomegaly, elevated liver enzymes and low platelets) syndrome or the rarer, more severe acute fatty liver of pregnancy (AFLP). This may require intensive care and early delivery of the fetus. Only a small number of women with HELLP and AFLP carry affected fetuses, but it is imperative that their newborn infants are screened by measurement of plasma acylcarnitines to exclude a fat oxidation defect. Screening only for the associated dicarboxylic aciduria, using urinary organic acid analysis, is not sensitive enough and has led to the diagnosis being overlooked.

Women with partial OTC deficiency may present for the first time a few days after delivery. They are able to withstand the increased metabolic stress of pregnancy and delivery, but the massive protein load presented by the involution of the uterus precipitates hyperammonaemia. Many of these women have never had previous symptoms that might alert their obstetrician to the cause of their illness, although some have an aversion to high protein diets.

Clinical abnormalities in the infant may also reveal an undetected IMD in the mother. Maternal PKU syndrome is a description of the clinical consequences to the fetus of in utero exposure to elevated plasma phenylalanine resulting from PKU in the mother. A mother not known to have PKU, usually because she was born in an area without a neonatal screening programme, may have had hyperphenylalaninaemia that was sufficiently mild for her not to have come to medical attention, but significant enough to affect the fetus. Typical features are low birth weight, microcephaly, cardiac abnormalities and developmental delay. The infant does not have PKU or hyperphenylalaninaemia, and therefore does not require dietary restriction. The diagnosis is usually made when the infant is investigated for microcephaly or developmental delay. Plasma phenylalanine needs to be measured in the mother for diagnosis; urinary amino acids may not be sufficiently sensitive and diagnoses have been missed when only this investigation has been used.

Newborn screening is used to detect conditions that have a presymptomatic period during which treatment can dramatically improve outcome. In the UK, conditions screened for at this time include congenital hypothyroidism (see below), PKU, MCADD, cystic fibrosis and sickle cell disorders. A pilot study is underway in the UK to examine an expanded neonatal screening programme including maple syrup urine disease, glutaric aciduria type 1, isovaleric acidaemia, LCHADD and pyridoxine unresponsive homocystinuria. This is modest compared to some countries, e.g. the USA where newborns are screened for over 30 conditions. However, for many of these conditions the natural history is not fully understood, treatments are only partially effective and infants may present and die prior to the screening result being available. The detection of infants who will never develop symptomatic disease remains a real concern. During the development of MCADD screening, mutations were identified in infants with raised octanoylcarnitine that have never been associated with clinical abnormalities.

Screening is also used to detect IMDs in populations with higher frequencies of a particular condition, usually secondary to a founder effect (a mutation occurring early in the settlement of a geographically isolated area or within a limited gene pool so that it occurs with high frequency), for example Tay–Sachs disease in the Ashkenazi Jewish population.

Newborn screening is widely practised for congenital hypothyroidism, but while some of these infants have inherited disorders of thyroid hormone synthesis, some have thyroidal agenesis or dysgenesis (that is, failure of development of the gland), for which a genetic basis has not been defined.

The molecular bases of IMDs are mutations in genes that adversely affect the functions of specific proteins. The patterns of inheritance vary, but the majority of these conditions are autosomal recessive.

If the frequency of the gene defect in the general population is known, the incidence can be calculated: for example the carrier frequency for PKU is 1 in 50, so the incidence equals (1/50 × 1/50) (the chance of two carriers having children together) multiplied by 1/4 (the chance of them having an affected child), that is, 1/10 000. If a certain condition is known to exist in a family, genetic counsellors can use calculations of this sort to inform individual couples of their risk of having an affected child. For example, if the sister of an individual PKU were to have a child with an unrelated man, the risk of the baby having the condition would be 1 in 300, which is considered negligible. (She is not affected: she has a 2 in 3 chance of being a carrier and 1 in 3 of being homozygous normal – the denominator is three rather than four because she is unaffected). The man’s chance of being a carrier is 1 in 50 (the carrier frequency in the general population), so the risk of two faulty genes being passed to an embryo is 2/3 × 1/50 × 1/4 = 1/300.)

Consanguinity within a family increases the risk of autosomal recessive conditions and there are some disorders with a high frequency within particular populations. There may be a founder effect within certain populations, for example the Pennsylvanian Mennonites, in whom the severe form of maple syrup urine disease has an incidence of 1:176. In these kindred, lineage can be traced to one couple who emigrated from Europe in the eighteenth century. The tradition of first cousin marriages in some immigrant groups is increasing the incidence of IMDs in some areas of the UK.

It should be noted that, although affected individuals with autosomal recessive IMDs are often classified as homozygotes, the existence of multiple mutations affecting individual genes means that some are, strictly speaking, compound heterozygotes.

Unlike autosomal recessive conditions, in X-linked disorders carriers may manifest the disorder clinically, for example in OTC deficiency. As discussed previously, in carrier females the variation in the degree of symptoms is due to lyonization, the random inactivation of one of the two X chromosomes in all cells, including hepatocytes. The severity of disease depends on the percentage of hepatocytes expressing the normal gene. This can lead to a varied clinical presentation within families, with some female carriers presenting with severe hyperammonaemia in the neonatal period and others being apparently unaffected.

Mitochondria are unique intracellular organelles, in that they have their own genes. However, a fully functional mitochondrion is the product of both the nuclear and mitochondrial genomes with the vast majority of genes, in the order of 1300, being encoded in the nucleus. If disease-causing mutations arise in the nucleus, these can be inherited in the usual way, for example as autosomal recessive or dominant, or X-linked traits. Mitochondrial DNA (mtDNA) is inherited in a matrilineal fashion; that is, mtDNA is inherited exclusively from the mother. Paternal mitochondrial DNA is present in the mitochondria in the sperm’s tail to provide ATP for propulsion. On fertilization, the tail of the sperm is left outside and hence no paternal mtDNA enters the zygote. Mitochondrial DNA mutations can therefore be inherited only from females, but can affect males or females. Point mutations inherited in this fashion include those for: myoclonic epilepsy, ragged red fibres (MERRF); mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) and Leber hereditary optic neuropathy.